Ir(iii)/Ag(i)-catalyzed directly C–H amidation of arenes with OH-free hydroxyamides as amidating agents

A versatile Ir(iii)-catalyzed C–H amidation of arenes by employing readily available and stable OH-free hydroxyamides as a novel amidation source. The reaction occurred with high efficiency and tolerance of a range of functional groups. A wide scope of aryl OH-free hydroxyzamides, including conjugated and challenging non-conjugated OH-free hydroxyzamides, were capable of this transformation and no addition of an external oxidant is required. This protocol provided a simple, straightforward and economic method to a variety N-(2-(1H-pyrazol-1-yl)alkyl)amide derivates with good to excellent yield. Mechanistic study demonstrated that reversible C–H bond functionalisation might be involved in this reaction.


Introduction
Pyrazole and its derivatives play crucial roles in organic and pharmaceutical elds, because of their unique ve-membered nitrogen-containing heterocyclic structures. 1 In synthetic chemistry, pyrazole and its derivatives are not only efficiently and conveniently synthesized, but also further transformed into more complex articial molecules. 2In the continuous development of coordination chemistry, various complexes containing pyrazole ligands have also been synthesized, characterized, and further applied. 3In the eld of biomedicine, pyrazole and its derivatives have also been proven to have good antibacterial, anti-inammatory, and anti-tumor activities. 4ecause of the multi-reactivity and practicality prole, there is a continued strong demand for efficient and selective synthesis of pyrazole and its derivatives for theoretical and practical research.The most common synthesis methods mainly focus on the following parts: (1) Knorr pyrazole synthesis reaction and further expanded to a,b-unsaturated carbonyl compounds; 5 (2) pyrazole and its derivatives can also be obtained from the reaction of hydrazones and ketones, alkynes, and isonitriles catalyzed by metal-free conditions; 6 (3) direct functionalization reactions of pyrazole and its derivatives. 7Based on previous work, there has been good progress in the research of transition metal catalyzed pyrazole synthesis methodologies. 8Actually, cost-effective, and feasibility degree synthesis methods are still needful, in view of the broad range of applications of pyrazole in biology and chemistry.
Transition-metal-catalyzed C-H functionalization has become powerful tools for synthesis of non-cyclic or cyclic articial molecule, which complementary to traditional synthesis methods. 9C-H functionalization reaction has unparalleled advantages in the construction of chemical bonds and compounds. 10Particularly, signicant progress has been made in C-H bond amidation reactions in recent years. 11Heterocyclic compounds represented by pyrazole are excellent directing groups in C-H bond activation reactions, which catalyzed by Cp*Rh(III), Cp*Ir(III), Ru(II) and other metal. 12At the same time, a series of amidation reagents, such as N-substituted hydroxylamines, 13 N-methoxyamide, 14 dioxazolones, 15 organic azide, 16 chloramines and other substrates, 17 have been widely used as C-N coupling partners for construction of structurally complex scaffolds.However, the application of OH-free hydroxyamide as a novel amidation reagent in C-H bond activation are relatively limited.Therefore, the development of an efficient one pot method to give ortho-functionalized pyrazole derivatives via Ir(III)/Ag(I)-catalyst C-H bond amination reactions of N-arylpyrazoles and OH-free hydroxyamides.In this methodology, OH-free hydroxyamides were innovatively used as the amidation source, which has excellent selectivity, stability and reactivity compared to organic azides via comparative experiment (Scheme 1).

Results and discussion
We started our investigation by submitting the model substrate N-phenyl-pyrazole (1a) and N-hydroxybenzamide (2a).The reaction carried out with [Cp*IrCl 2 ] 2 (4 mol%) as catalyst, AgNTf 2 as an (20 mol%) additive, without any external base and oxidant, in 1,2-DCE at 90 °C for 8 h under air.As result, the desired amidated product (3aa) was obtained in 57% isolated yield without any bisamidated product was detected.Aer constructing this feasible concept, the conrmed results encourage us to further conduct optimization studies with an initial focus on the catalyst, among the various catalyst investigated, the [Cp*IrCl 2 ] 2 was found most efficient, other metal catalyst such as[Cp*RhCl 2 ] 2 , Pd(OAc) 2 and Pd(PPh 3 ) 4 could not promoted this transformation (Table 1, entry 1-4).The control experiment further conrmed no amidating product could be obtained without [Cp*IrCl 2 ] 2 or AgNTf 2 (Table 1, entry 5-6).In order to improve the yield of the reaction, several solvents were taken into consideration, such as toluene, PhCl, MeCN, DMSO and 1,4-dioxane were screened (Table 1, entry 7-11), wherein PhCl was the best choice with 67% isolated yield.Subsequently, a variety of additive were used, unfortunately, none of them worked (Table 1, entry 12-17).The effect of temperate variation was also investigated and increasing it to 120 °C could assisted the transformation.However, further increase of temperature the yield with slightly decrease (Table 1, entry 18-21).In addition, reducing or increasing catalyst, additive and time were detrimental to the yield (Table 1, entry 22-28).
With the optimized reaction conditions in hand, we next examined the tolerance of this methodology, and the corresponding results are summarized in the Table 2.We rst explored the scope of N-aryl pyrazole with 2a as coupling partner.It was found that a series of para-position substituted underwent smoothly amidation with 2a deliver the corresponding products in good to excellent yields (83-94%) with high tolerance of functional groups.Even for sensitive iodinesubstituted substrates also could provide the corresponding product 3la in 87% yield.Especially, the substrates containing triuoromethyl, Cyano group with 2a deliver the corresponding products 3ma and 3na in 84% and 83% yield, respectively.For the meta-substituted substrates, the yields show slightly  decreases 3ba, 3ga and 3ha compared with para-substituents 3ca, 3ja and 3ka.In the end, we also investigated the reaction activity of naphthalene ring, the product 3oa in 94% yield was obtained and conrmed the structure by single crystal diffraction.A gram-level experiment was conducted, and the corresponding product can still be obtained in 88% yield (1.37 g).
Encouraged by these positive outcomes, we further examined the selective of the Ir(III)/Ag(I)-catalyzed C-H bond amidation reaction with N-phenyl-pyrazole (1a), a variety of substituted aryl N-hydroxyzamide 2 were examined, as shown in Table 3. N-hydroxyzamide 2 bearing both electron-donating as well as electron-withdrawing aryl substituents were reacted well with 1a to give the desired amidated products (3ab-3ao) in good to excellent yields.To our delight, bisubstituted aryl N-hydroxyzamide could be successfully converted to the corresponding products 3ai and 3aj with more than 80% yield, respectively.What we need to mention that ortho-position substituted substrates also provided the corresponding product 3ab and 3ag in 91 and 95% yield, respectively.In addition, when we employed N-hydroxycarbamate as amidating agent, there are no amidated products generated under Ir(III)/Ag(I)-catalyst system.
To illustrate the stability and reactivity of N-hydroxyamide, we also applied acyl azides under Ir(III)/Ag(I)-catalyst system.To our delight, desired amidated products were obtained under suitable condition in accepted yield, without any Curtius rearrangement product, 18 and the results shown in Scheme 5.In the selected example, the yield of the acyl azide as the amidation reagent is lower than that of the N-hydroxylamine as the amidation reagent (Scheme 3).
To investigate the mechanism of this reaction, we carried out a series of control experiments.First, substrate 1a was treated with CD 3 OD under standard reaction conditions.As a result, no  Based on the above results and literature precedence, 19 a plausible mechanism is presented in Scheme 5. First, the treatment of [Cp*RhCl 2 ] 2 with AgNTf 2 gives rise to the cationic Rh(III) species A, which undergo C-H bond activation with 1 to generated HNTf 2 and ve-membered rhodacycle B, then coordinated to N-hydroxylamine 2 to afford intermediate C followed by migratory insertion, resulting in the formation of complex D and the release of H 2 O. Finally, proto-demetalation step lead to nal product 3 and regenerated the Rh(III)-catalyst.

Conclusions
In summary, the combination of iridium catalyst and AgNtf 2 additive deliver a highly efficient catalytic system for the C-H activation of N-aryl pyrazole with N-hydroxyamide, which allows the high efficient synthesis 2-amide substituted N-aryl pyrazole derivatives without any bisamidated products.This C-H bond amidation protocol is applicable to the coupling of a wide range of OH-free hydroxylamine, the reaction proceeds under oxidantfree or base-free conditions, enabling facile access to amidated products in good to high yields with a broad functional group tolerance.We believe that this strategy has potential applications in organic synthesis, as well as medicinal chemistry.

a
Scheme 2 Scope of other N-heterocycles-DGs substrates.a,b

Table 3
Substrates scope of N-hydroxyamide